insulin-glargine and Breast-Neoplasms

Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms.. A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies.. In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations.. There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Glargine; MCF-7 Cells; Risk

An association of insulin use and risk of cancer has been reported but evidence is conflicting and methodological issues have been identified.. To summarize results regarding insulin use and cancer risk by a systematic review and meta-analysis of cohort and case-control studies examining risk of cancer associated with insulin use in patients with diabetes.. Systematic literature search in 5 databases: PubMed, Embase, Web of Science, Scopus and Cochrane Library. STUDY ELIGIBILITY CRITERIA (PICOS):. diabetes patients.. Users of any exogenous insulin. Comparison: Diabetes patients with or without use of antidiabetic drugs.. Any incident cancer.. Cohort and case-control studies.. 42 eligible studies examined risk of any cancer and 27 site-specific cancers. Results of individual studies were heterogeneous. Meta-analyses were significant for: Insulin vs No Insulin: Increased risk for pancreas, liver, kidney, stomach and respiratory cancer, decreased risk for prostate cancer. Insulin vs Non-Insulin Antidiabetics: Increased risk for any, pancreatic and colorectal cancer. Glargine vs Non-Glargine Insulin: Increased risk for breast cancer, decreased risk for colon cancer.. Few studies available for most cancer sites and exposure contrasts, and few assess effect of dose and duration of exposure. Methodological issues in several studies. Availability of confounders.. Insulin use was associated with risk of cancer at several sites. Cautious interpretation of results is warranted as methodological issues and limitations in several of the included studies have been identified. Choice of study design may have a profound effect on estimated cancer risk.

Topics: Breast Neoplasms; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Diabetes Mellitus; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Neoplasms; Observational Studies as Topic; Publication Bias; Registries; Research Design

To assess whether initiation of insulin glargine (glargine), compared with initiation of NPH or insulin detemir (detemir), was associated with an increased risk of breast cancer in women with diabetes.. This was a retrospective new-user cohort study of female Medicare beneficiaries aged ≥65 years initiating glargine (203,159), detemir (67,012), or NPH (47,388) from September 2006 to September 2015, with follow-up through May 2017. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for incidence of breast cancer according to ever use, cumulative duration of use, cumulative dose of insulin, length of follow-up time, and a combination of dose and length of follow-up time.. Ever use of glargine was not associated with an increased risk of breast cancer compared with NPH (HR 0.97; 95% CI 0.88-1.06) or detemir (HR 0.98; 95% CI 0.92-1.05). No increased risk was seen with glargine use compared with either NPH or detemir by duration of insulin use, length of follow-up, or cumulative dose of insulin. No increased risk of breast cancer was observed in medium- or high-dose glargine users compared with low-dose users.. Overall, glargine use was not associated with an increased risk of breast cancer compared with NPH or detemir in female Medicare beneficiaries.

Topics: Age Factors; Age of Onset; Aged; Aged, 80 and over; Breast Neoplasms; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incidence; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Medicare; Retrospective Studies; United States

Long-term insulin exposure has been implicated in breast cancer etiology, but epidemiological evidence remains inconclusive. The aims of this study were to investigate the association of insulin therapy with mammographic density (MD) as an intermediate phenotype for breast cancer and to assess associations with long-term elevated circulating insulin levels using a genetic score comprising 18 insulin-associated variants.. We used data from the KARolinska MAmmography (Karma) project, a Swedish mammography screening cohort. Insulin-treated patients with type 1 (T1D, n = 122) and type 2 (T2D, n = 237) diabetes were identified through linkage with the Prescribed Drug Register and age-matched to 1771 women without diabetes. We assessed associations with treatment duration and insulin glargine use, and we further examined MD differences using non-insulin-treated T2D patients as an active comparator. MD was measured using a fully automated volumetric method, and analyses were adjusted for multiple potential confounders. Associations with the insulin genetic score were assessed in 9437 study participants without diabetes.. Compared with age-matched women without diabetes, insulin-treated T1D patients had greater percent dense (8.7% vs. 11.4%) and absolute dense volumes (59.7 vs. 64.7 cm. The consistency in direction of association for insulin treatment and the insulin genetic score with the absolute dense volume suggest a causal influence of long-term increased insulin exposure on mammographic dense breast tissue.

Topics: Adult; Aged; Breast; Breast Density; Breast Neoplasms; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Mammography; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Sweden; Time Factors

Purpose The association between long-acting insulin analogs and increased breast cancer risk is uncertain, particularly with the short follow-up in previous studies. We assessed this risk long term in women with type 2 diabetes. Methods A population-based cohort of women 40 years or older, all of whom were treated with long-acting (glargine, detemir) or neutral protamine Hagedorn (NPH) insulin between 2002 and 2012, was formed using the United Kingdom's Clinical Practice Research Datalink. Women were followed until February 2015 or breast cancer diagnosis. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% CIs of incident breast cancer, comparing long-acting insulin analogs with NPH overall, as well as by duration and cumulative dose. Results The cohort included 22,395 women who received insulin treatment, with 321 incident breast cancer events occurring during up to 12 years of follow-up (incidence rate 3.3 per 1,000 person-years). Compared with NPH insulin, insulin glargine was associated with an increased risk of breast cancer (HR, 1.44; 95% CI, 1.11 to 1.85), mainly increasing 5 years after glargine initiation (HR, 2.23; 95% CI, 1.32 to 3.77) and after > 30 prescriptions (HR, 2.29; 95% CI, 1.26 to 4.16). The risk was particularly elevated among prior insulin users (HR, 1.53; 95% CI, 1.10 to 2.12) but not for new users, which included fewer patients and for which one cannot rule out an HR of 1.81. The risk associated with insulin detemir was not significantly elevated (HR, 1.17; 95% CI, 0.77 to 1.77). Conclusion Long-term use of insulin glargine is associated with an increased risk of breast cancer in women with type 2 diabetes. The risk associated with insulin detemir remains uncertain because there are fewer users of this insulin.

Topics: Aged; Breast Neoplasms; Canada; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incidence; Insulin Detemir; Insulin Glargine; Insulin, Isophane; Middle Aged; Risk

Topics: Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Glargine

This study was aimed to assess the risk of breast cancer associated with exposure to insulin glargine in women with type 2 diabetes and evaluate whether the pattern of risk concurs with the hypothesized trend of an increase in risk with longer duration of use, taking into account previous cumulative exposure to other types of insulin.. We performed a restrospective cohort study (2002-2013) in the Clinical Practice Research Datalink among adult female patients with a first ever insulin prescription (n = 12 468). Time-dependent exposure measures were used to assess associations with duration of use of: (1) other insulin types before glargine was first prescribed (i.e. among switchers); and (2) of glargine during follow-up. Analyses were performed separately for insulin-naïve glargine users and patients switched to glargine. Cox proportional hazards models were used to derive p-trends, hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer associated with glargine use.. During 66 151 person years, 186 breast cancer cases occurred; 76 in glargine users (3.0/1000 years) and 110 in users of other insulins (2.7/1000 years). Among insulin-naïve women, no association with cumulative glargine use was observed (p-trend = 0.91), even after ≥5 years (HR = 1.06, 95% CI 0.48-2.33). Among switchers, a linear trend with years of prior exposure to other insulins was found (p-trend = 0.02). An increased risk was observed in glargine users with extensive (>3 years) past exposure to other insulins (HR = 3.17, 95% CI 1.28-7.84). A non-significant trend with cumulative glargine exposure was found among switchers (p-trend = 0.24).. Exposure to glargine was not associated with an increased breast cancer risk in insulin-naïve patients. Exposure to other insulins prior to the start of glargine appears to be relevant when studying breast cancer risk associated with glargine use.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Cohort Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin Glargine; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Factors; United Kingdom

OBJECTIVE Several studies have been published in 2009 suggesting a possible association between insulin glargine and increased risk of malignancies, including breast cancer. The objective of this study was to assess the relation between the individual insulins (glargine, aspart, lispro, and human insulin) and development of breast cancer. RESEARCH DESIGN AND METHODS Seven hundred seventy-five incident cases of primary invasive or in situ carcinoma breast cancer occurring in women with diabetes from 92 centers in the U.K., Canada, and France were matched to a mean of 3.9 diabetic community control subjects (n = 3,050; recruited from 580 general practices) by country, age, recruitment date, and diabetes type and management. The main risk model was a multivariate conditional logistic regression model with case/control status as the dependent variable and individual insulin use, 8 years preceding the index date, as the independent variable, controlling for past use of any insulin, oral antidiabetes drugs, reproductive factors, lifestyle, education, hormone replacement therapy and history of contraceptive use, BMI, comorbidities, diabetes duration, and annual number of physician visits. Glargine was also compared with every other insulin by computing all ratios using the variance-covariance matrix of logistic model parameters. RESULTS Adjusted odds ratios of breast cancer for each type of insulin versus no use of that insulin were 1.04 (95% CI 0.76-1.44) for glargine, 1.23 (0.79-1.92) for lispro, 0.95 (0.64-1.40) for aspart, and 0.81 (0.55-1.20) for human insulin. Two-by-two comparisons found no difference between glargine and the different types of insulins. Insulin dosage or duration of use and tumor stage did not change the results. CONCLUSIONS This international study found no difference in the risk of developing breast cancer in patients with diabetes among the different types of insulin with short- to mid-term duration of use. Longer-term studies would be of interest.

Topics: Aged; Breast Neoplasms; Canada; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; France; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin Glargine; Insulin Lispro; Insulin, Long-Acting; Insulin, Regular, Human; Insulins; Middle Aged; Risk Factors; United Kingdom

Insulin analogues are widely used in clinical practice. Modifications on the insulin molecular structure can affect the affinity and activation towards two closely related receptor tyrosine kinases: the insulin receptor (INSR) and the insulin-like growth factor 1 receptor (IGF1R). A switch towards higher IGF1R affinity is likely to emphasize mitogenesis rather than glucose metabolism. Relevant well-validated experimental tools to address the insulin analogue activation of either INSR or IGF1R are missing. We have established a panel of human MCF-7 breast cancer cell lines either ectopically expressing the INSR (A or B isoform) in conjunction with a stable knockdown of the IGF1R or ectopically expressing the IGF1R in conjunction with a stable knockdown of the INSR. In these cell lines, we systematically evaluated the INSR and IGF1R receptor activation and downstream mitogenic signalling of all major clinical relevant insulin analogues in comparison with insulin and IGF1R. While most insulin analogues primarily activated the INSR, the mitogenic activation pattern of glargine was highly similar to IGF1 and insulin AspB10, known to bind IGF1R and induce carcinogenesis. Yet, in a long-term proliferation assay, the proliferative effect of glargine was not much different from regular insulin or other insulin analogues. This was caused by the rapid enzymatic conversion into its two metabolic active metabolites M1 and M2, with reduced mitogenic signalling through the IGF1R. In summary, based on our new cell models, we identified a similar mitogenic potency of insulin glargine and AspB10. However, rapid enzymatic conversion of glargine precludes a sustained activation of the IGF1R signalling pathway.

Topics: Antigens, CD; Biotransformation; Breast Neoplasms; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Genetic Engineering; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; MCF-7 Cells; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Receptor, Insulin; Receptors, Somatomedin; RNA Interference; Signal Transduction; Time Factors; Transfection

Recent epidemiological studies have suggested that some insulin analogues could be associated with an increased risk of cancer. The aim of this retrospective study was to examine whether patients with diabetes mellitus (DM) using insulin glargine have a higher tumor stage of breast carcinoma in comparison to patients using other types of insulin.. We performed a chart review of 79 surgically treated breast carcinoma patients (mean age of 66.5 years; range 38-86 years) who were on insulin. Insulin glargine was used in 13 patients, while the other 66 patients were on other types of insulin. Clinical and histopathology characteristics of patients on glargine versus other types of insulin were compared using a chi-square test and non-parametric statistical analysis.. DM type 1 and DM type 2 was present in 14 and 65 patients, respectively. The mean tumor size was 2.98 cm. The TNM tumor stage at diagnosis was not higher among patients on glargine compared to patients on other types of insulin (T1/T2 85% vs. 68%, T3/T4 15% vs. 32%, p = 0.32; N1 54% vs. 58%, p = 0.80; M1 8% vs. 6%, respectively). No significant differences between both study groups (glargine vs. other types of insulin) were found in the ages of the patients, their BMI, tumor histology, grade, number of metastatic lymph nodes, hormone receptors or HER-2 status.. We could not show that patients with DM using insulin glargine have a higher tumor stage of breast carcinoma in comparison to those using other types of insulin.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Breast Neoplasms; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Gene Expression; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Lymphatic Metastasis; Middle Aged; Neoplasm Grading; Neoplasm Staging; Receptor, ErbB-2

To examine whether use of insulin glargine, compared with another long-acting insulin, is associated with risk of breast, prostate, colorectal cancer, or all cancers combined.. Computerized health records from Kaiser Permanente Northern and Southern California regions starting in 2001 and ending in 2009 were used to conduct a population-based cohort study among patients with diabetes aged ≥18 years. With use of Cox regression modeling, cancer risk in users of insulin glargine (n = 27,418) was compared with cancer risk in users of NPH (n = 100,757).. The cohort had a median follow-up of 3.3 years during which there was a median of 1.2 years of glargine use and 1.4 years of NPH use. Among users of NPH at baseline, there was no clear increase in risk of breast, prostate, colorectal, or all cancers combined associated with switching to glargine. Among those initiating insulin, ever use or ≥2 years of glargine was not associated with increased risk of prostate or colorectal cancer or all cancers combined. Among initiators, the hazard ratio (HR) for breast cancer associated with ever use of glargine was 1.3 (95% CI 1.0-1.8); the HR for breast cancer associated with use of glargine for ≥2 years was 1.6 or 1.7 depending on whether glargine users had also used NPH.. Results of this study should be viewed cautiously, given the relatively short duration of glargine use to date and the large number of potential associations examined.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; California; Colorectal Neoplasms; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Incidence; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms; Retrospective Studies; Risk; Risk Assessment; Time Factors; Young Adult

Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study.. Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes.. Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified.. Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.

Topics: Breast Neoplasms; Cohort Studies; Community Pharmacy Services; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Electronic Health Records; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Incidence; Insulin; Insulin Glargine; Insulin, Long-Acting; Insulin, Regular, Human; Male; Medical Record Linkage; Middle Aged; Neoplasms; Netherlands; Patient Admission; Proportional Hazards Models; Risk

To elucidate methodological questions in assessing the relationship between insulin treatment and cancer, since the risk of tumour growth generally increases with longer exposure time and higher dose of a growth promoting substance.. Continuous hazard functions for risk of breast and prostate cancer were estimated in relation to exposure of insulin glargine among diabetic patients included in the record system, Diab-Base, as well as in the general population in Sweden.. In 7942 female diabetic patients, mean follow-up 7.0 years, 2014 patients initiated insulin glargine with a mean follow-up of 3.5 years. Among 11,613 men, mean follow-up 6.9 years, 2760 had a mean follow-up with glargine of 3.4 years. Risk of prostate cancer decreased significantly with longer exposure to insulin glargine (p=0.032), although average risk versus non-glargine was non-significantly higher (HR 1.37, 95% CI 0.78-2.39). The breast cancer risk did not change with longer exposure to insulin glargine (p=0.35) and the mean risk was similar for glargine and non-glargine (p=0.12). With higher dose of insulin glargine, there was an increase in risk of prostate (p=0.037) and breast cancer (p=0.019). In diabetics, the mean risk of prostate cancer was decreased (HR 0.68, 95% CI 0.59-0.79) but similar for breast cancer (HR 0.95, 95% CI 0.78-1.14) compared to the general population and did not change with longer diabetes duration (p=0.68 and p=0.53 respectively).. Analysing continuous hazard functions for cancer risk in relation to exposure time to an antidiabetic agent is an important complementary tool in diabetes and cancer research.

Topics: Adult; Aged; Breast Neoplasms; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms; Risk Factors; Sweden; Time Factors

Topics: Breast Neoplasms; Diabetes Mellitus, Type 1; Female; Humans; Insulin Glargine; Insulin, Long-Acting; Male; Prostatic Neoplasms

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Cohort Studies; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Incidence; Insulin Glargine; Insulin, Long-Acting; Middle Aged; Prognosis; Risk Factors; Sweden; Time Factors

There have been growing concerns regarding the long-term effects of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) on the risk of breast cancer.. We used the UK's General Practice Research Database (GPRD) to identify a cohort of women aged 40 years or over with type 2 diabetes, treated with insulin during 2002-2006 and followed until the first breast cancer diagnosis or 31 December 2009. After the users of insulin glargine had been matched with users of other insulins on age, calendar time and duration of prior insulin use, the HR of breast cancer associated with insulin glargine use was estimated using a Cox proportional hazards model, adjusted for known risk factors for breast cancer.. The cohort comprised 15,227 women, including 4,579 glargine users and 10,648 users of other insulins, of which 246 developed breast cancer during up to 8 years follow-up (incidence rate 4.1 per 1,000 per year). Insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use (HR 0.9; 95% CI 0.7-1.3). The risk tended to increase after 5 years (HR 1.8; 95% CI 0.8-4.0), and significantly so for the women who had been on insulin before starting glargine (HR 2.7; 95% CI 1.1-6.5).. The risk of breast cancer in women with type 2 diabetes is not increased during the first 5 years of insulin glargine use. However, longer-term use may increase this risk, particularly in women with longstanding use of insulin before starting insulin glargine.

Topics: Aged; Breast Neoplasms; Cohort Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Incidence; Insulin Glargine; Insulin, Long-Acting; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Factors; Time; United Kingdom

Glargine is widely used as a long-acting insulin analogue in the treatment of diabetes mellitus. However, this insulin analogue has been recently suspected to be associated with an increased risk of cancer. The aim of this study was to investigate the influence of glargine on proliferation of breast adenocarcinoma cell line (MCF-7) and its possible mechanism. Effects of glargine and regular human insulin on the cell proliferation were tested in ER-positive MCF-7 cells by MTT assay. Apoptosis in MCF-7 cells was measured by flow cytometry. The protein levels of p-AKT, Bcl-2, and Bax were also determined by Western blotting and immunohistochemistry, respectively. The result showed that glargine (100, 200 nmol/l) stimulated proliferation of ER-positive MCF-7 cells compared with regular human insulin. At the same time, glargine decreased the percentage of early apoptosis in MCF-7 cells. Otherwise, glargine (100 nmol/l) stimulated the p-AKT in a time-dependent manner in MCF-7 cells. Furthermore, we found that glargine downregulated the level of Bax protein and upregulated that of Bcl-2 (p <0.05). These data show that glargine promote the proliferation of breast adenocarcinoma cells in vitro, probably by preventing apoptosis.

Topics: Adenocarcinoma; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Enzyme Activation; Female; Humans; Insulin Glargine; Insulin, Long-Acting; Phosphorylation; Proto-Oncogene Proteins c-akt; Up-Regulation

In vitro evidence suggests insulin glargine promotes tumors; observational human studies are conflicting. We aimed to expand understanding of this potential treatment risk.. This retrospective cohort study of type 2 diabetic patients >68 years old used Medicare inpatient, outpatient (2003-2008), and prescription data (2006-2008). Adjusting for patient characteristics, dose, and metformin use, Cox models yielded hazard ratios (HRs) for incident cancer (breast, prostate, pancreas, colon, any site) associated with three forms of insulin: nonglargine, glargine, or glargine plus nonglargine (combination).. Overall, 81,681 patients were followed for a mean of 23.1 months. Mean age was 77.4 years. Treatment group distribution was 20.7% glargine, 60.5% nonglargine, 18.7% combination insulin. We observed 5,466 incident cancers; crude rates did not vary by treatment group. In fully adjusted models, nonglargine use was the referent; glargine was not associated with significant increased risk of any cancer measure. In secondary analyses including only the top quartile of daily insulin dose patients, glargine was not associated with any cancer risk difference; combination insulin was associated with higher breast cancer risk (HR 1.75 [95% CI 1.10-2.78]) and lower colon cancer risk (0.33 [0.13-0.80]). In age-stratified analyses of highest-dose users, combination insulin conferred a higher risk of breast cancer in those ≤75 years old (2.87 [1.45-1.59]).. The general lack of association between glargine-only use and cancer is reassuring. Breast cancer risk associated with high-dose combination insulin in secondary analyses could result from multiple comparisons, residual confounding, or true association; further research is warranted.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Humans; Insulin Glargine; Insulin, Long-Acting; Male; Neoplasms; Retrospective Studies

Insulin glargine (Lantus) stimulates growth of MCF-7 cells stronger than human insulin. We investigated if serum from diabetic patients treated with glargine versus human insulin may display a similar effect.. Pairs of serum samples from 31 C-peptide negative type-1 diabetic patients were investigated. In cross-over fashion, 23 patients were treated with glargine plus rapid-acting insulin analogues, and similar doses of human NPH and rapid-acting insulin. For comparison, eight patients were treated with insulin detemir (Levemir) and human NPH. MCF-7 cells were incubated with 10% serum and proliferation was assessed after 72 hours.. Serum containing insulin glargine was 1.11(95% CI 1.05-1.18) fold more mitogenic than human insulin-containing serum (p < 0.005); mitogenicity of serum containing detemir was 0.99(95% CI 0.98-1.02) fold that of human insulin-containing serum.. The serum of diabetic patients was slightly stronger mitogenic when using glargine as compared to human insulin or detemir for treatment.

Topics: Breast Neoplasms; C-Peptide; Cell Line, Tumor; Cells; Chemotactic Factors; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Pilot Projects; Risk Factors

Topics: Breast Neoplasms; Canada; Case-Control Studies; Confounding Factors, Epidemiologic; Diabetes Mellitus; Female; France; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; International Cooperation; Multicenter Studies as Topic; Risk Factors; United Kingdom

Insulin analogues are widely used in the treatment of diabetes mellitus. Some insulin analogues were reported to display atypical activities in vitro that resemble those of insulin-like growth factor-I (IGF-I). The aim of this study was to investigate whether two long-acting insulin analogues [glargine (Lantus, Sanofi Aventis, Germany) and detemir (Levemir, Novo Nordisk, Denmark)] and two short-acting analogues [lispro (Humalog, Eli Lilly, Indianapolis, USA) and aspart (Novolog, Novo Nordisk, Denmark)] exhibit IGF-I-like activities on cultured cancer cells in comparison with IGF-I and regular human insulin.. HCT-116 (colorectal cancer), PC-3 (prostate cancer) and MCF-7 (breast adenocarcinoma) cell lines were treated with insulin, IGF-I or insulin analogues, and proliferation and protection from apoptosis were measured by cell counting and fluorescent-activated cell sorter (FACS) analysis, respectively. In addition, Western blots were used to identify signalling molecules activated by the analogues.. Glargine, detemir and lispro had proliferative effects that resemble IGF-I action. Insulin, however, did not stimulate cellular proliferation. In addition, glargine and detemir displayed an IGF-I-like anti-apoptotic activity. Glargine, like insulin and IGF-I, induced phosphorylation of both ERK and AKT, suggesting that the analogue is able to stimulate both the ras-raf-mitogen-activated protein kinase (MAPK) and PI3K-AKT pathways. Furthermore, glargine induced both insulin receptor (IR) and IGF-IR phosphorylation.. Glargine, detemir and lispro, unlike regular insulin, exhibit in vitro proliferative and anti-apoptotic activities in a number of cancer cell lines. These actions resemble some of the effects of IGF-I, a growth factor involved in cancer initiation and progression. Insulin had no increased IGF-I activity. The specific receptor/s involved in mediating analogues actions remains to be identified.

Topics: Adenocarcinoma; Apoptosis; Breast Neoplasms; Cell Division; Cell Line, Tumor; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Insulin; Insulin Detemir; Insulin Glargine; Insulin Lispro; Insulin-Like Growth Factor I; Insulin, Long-Acting; Male; Prostatic Neoplasms; Tumor Cells, Cultured

In the light of a report suggesting that insulin glargine may increase cancer occurrence, the EASD asked us to perform this study.. We followed 114,841 individuals who had a prescription dispensed for insulin between 1 July and 31 December 2005. From 1 January 2006 to 31 December 2007, we noted the occurrence of malignancies. Seven different nationwide registers were used to obtain information on insulin exposure, outcome and possible confounders; these were linked using the unique personal identity number assigned to every Swedish resident.. After adjustment for age and, when appropriate, sex, users of insulin glargine alone (no other types of insulin), compared with users of types of insulin other than insulin glargine, had an RR of 1.99 (95% CI 1.31-3.03) for breast cancer, 0.93 (95% CI 0.61-1.40) for gastrointestinal cancer, 1.27 (95% CI 0.89-1.82) for prostate cancer and 1.07 (95% CI 0.91-1.27) for any type of malignancy. Adjustment for age, smoking, BMI, age at onset of diabetes, age at birth of first child, cardiovascular disease and oestrogen use gave an RR for breast cancer of 1.97 (95% CI 1.29-3.00). The 95% CIs crossed 1.0 for the RR calculated in all analyses of users of insulin glargine in combination with other types of insulin.. In Sweden, during 2006 and 2007, women using insulin glargine alone (no other types of insulin) had an increased incidence rate of breast cancer as compared with women using types of insulin other than insulin glargine. This result may be due to a random fluctuation; the possibilities for examining validity are limited, and no statistically significant results were obtained for any other individual cancer site or for the outcome 'all malignancies'. No definitive conclusions regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies can be drawn from the results of this study.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Breast Neoplasms; Cardiovascular Diseases; Diabetes Complications; Diabetic Angiopathies; Educational Status; Female; Follow-Up Studies; Gastrointestinal Neoplasms; Humans; Hypoglycemic Agents; Incidence; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Myocardial Infarction; Neoplasms; Prostatic Neoplasms; Registries; Smoking; Sweden

The aim of the present study was to examine whether patients with diabetes in Scotland using insulin glargine have a greater cancer risk than patients using other types of insulin.. We used a nationwide diabetes clinical database that covers the majority of the Scottish population with diagnosed diabetes, and examined patients with diabetes who were exposed to any insulin therapy between 1 January 2002 and 31 December 2005. Among these we defined a fixed cohort based on exposure during a 4 month period in 2003 (n = 36,254, in whom 715 cases of cancer occurred) and a cohort of new insulin users across the period (n = 12,852 in whom 381 cancers occurred). Records from these cohorts were linked to cancer registry data up to the end of 2005. We used Cox proportional hazards models for survival analyses.. Those receiving any insulin glargine (n = 3,959) had the same incidence rate for all cancers as those not receiving insulin glargine (HR 1.02, 95% CI 0.77-1.36, p = 0.9 in the fixed cohort) The subset of patients using insulin glargine alone (n = 447) had a significantly higher incidence of all cancers than those using other insulins only (n = 32,295) (HR 1.55, 95% CI 1.01-2.37, p = 0.045), and those using insulin glargine with other insulins (n = 3,512) had a slightly lower incidence (HR 0.81, 95% CI 0.55-1.18, p = 0.26). There were important differences in baseline characteristics between these three groups, although the risk ratios were broadly unaltered on adjustment for these. Overall, there was no increase in breast cancer rates associated with insulin glargine use (HR 1.49, 95% CI 0.79-2.83, though insulin glargine only users had a higher rate than those using non-glargine insulin only (HR 3.39, 95% CI 1.46-7.85, p = 0.004). Among type 2 diabetic incident insulin users, no significant difference between the three groups was observed with respect to all cancer or breast cancer. All the above HRs are adjusted for age, calendar time prior cancer and type of diabetes, as appropriate, and are stratified according to sex.. Overall, insulin glargine use was not associated with an increased risk of all cancers or site-specific cancers in Scotland over a 4 year time frame. Given the overall data, we consider the excess of cases of all cancers and breast cancer in the subgroup of insulin glargine only users to more likely reflect allocation bias rather than an effect of insulin glargine itself.

Topics: Breast Neoplasms; Chromosome Mapping; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Neoplasms; Probability; Registries; Retrospective Studies; Scotland; Survival Analysis

Topics: Bias; Breast Neoplasms; Clinical Trials as Topic; Delayed-Action Preparations; Diabetes Mellitus; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Neoplasms; Risk

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Breast Neoplasms; Diabetes Complications; Diabetes Mellitus; Dose-Response Relationship, Drug; Europe; Female; Humans; Insulin; Insulin Glargine; Insulin, Long-Acting; Mammary Neoplasms, Experimental; Metformin; Middle Aged; Randomized Controlled Trials as Topic; Rats; Young Adult

The aim of the study was to investigate if the insulin analogue glargine, with an increased affinity for the IGF-I receptor (IGF-IR), affects the cell growth to a larger extent than human insulin in malignant cells expressing IGF-IRs. The breast cancer cell lines MCF-7 and SKBR-3, and the osteosarcoma cell line SaOS-2 were used. Gene expression was determined by real-time RT-PCR and receptor protein quantified by ELISAs. Receptor phosphorylation was assessed by immunoprecipitation and Western blot. Mitogenic effect was determined as (3)H-thymidine incorporation into DNA. The gene expression of insulin receptor (IR) varied between 4.3-7.5 x 10(-3) and the expression of IGF-IR between 7.7-147.7 x 10(-3) in relation to GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Insulin receptor and IGF-IR protein varied between 2.0-4.1 ng/mg protein and 2.0-40.4 ng/mg protein, respectively. The IGF-IR was phosphorylated by IGF-I at a concentration of 10(-10)-10(-9) M. All three polypeptides stimulated DNA synthesis in MCF-7, SKBR-3, and SaOS-2 cells. SaOS-2 cells were more sensitive to IGF-I than to insulin and glargine. MCF-7 cells were more sensitive to des(1-3)IGF-I than to IGF-I. In SKBR-3 and SaOS-2 cells, glargine tended to be more potent than human insulin to stimulate DNA synthesis. Our results suggest that glargine, compared to human insulin, has little or no increased mitogenic effect in malignant cells expressing IGF-IRs.

Topics: Analysis of Variance; Breast Neoplasms; Cell Division; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin-Like Growth Factor I; Insulin, Long-Acting; Mitogens; Osteosarcoma; Receptor, IGF Type 1; Statistics, Nonparametric; Tumor Cells, Cultured

Topics: Breast Neoplasms; Cell Proliferation; Dose-Response Relationship, Drug; Epithelial Cells; Humans; Insulin; Insulin Glargine; Insulin, Long-Acting; Mammary Glands, Human; Mitogens; Tumor Cells, Cultured